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  • 1.
    Agholme, Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Benedikz, Eirikur
    Department of Neurobiology, Division of Neurodegeneration, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Geriatriska kliniken.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy2012Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, nr 2, s. 343-358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

  • 2.
    Agholme, Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Geriatriska enheten.
    Lindström, Tobias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Geriatriska kliniken.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons2010Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, nr 4, s. 1069-1082Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

  • 3.
    Alleva, R.
    et al.
    Rizzoli Orthopaedic Institute, Bologna, Italy.
    Tomasetti, M.
    Institute of Experimental Pathology, University of Ancona, Ancona, Italy.
    Andera, L.
    Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
    Gellert, N.
    Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Pettenkoferstrasse 9, 80336 Munich, Germany.
    Borghi, B.
    Rizzoli Orthopaedic Institute, Bologna, Italy.
    Weber, C.
    Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Pettenkoferstrasse 9, 80336 Munich, Germany.
    Murphy, M.P.
    Mitochondrial Dysfunction Group, MRC Dunn Human Nutrition Unit, Cambridge, United Kingdom.
    Neuzil, Jiri
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection2001Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 503, nr 1, s. 46-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to a-tocopheryl succinate (a-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to a-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by a-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents. © 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

  • 4.
    Amandusson, Åsa
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Hermanson, Ola
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Estrogen-induced alterations of spinal cord enkephalin gene expression1999Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, nr 2, s. 243-248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

  • 5. Bestill onlineKjøp publikasjonen >>
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomal Membrane Stability and Cathepsins in Cell Death2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Lysosomes are acidic organelles that are critically involved in a number of physiological processes, including macromolecule degradation, endocytosis, autophagy, exocytosis and cholesterol homeostasis. Several pathological conditions, such as cancer, neurodegenerative disorders and lysosomal storage diseases, involve lysosomal disturbances, indicating the importance of the organelle for correct cellular function. The aim of this thesis was to investigate the role of lysosomes in cell death signaling.

    Previous studies have shown that permeabilization of the lysosomal membrane and release of hydrolytic enzymes such as cathepsin D to the cytosol occurs during apoptosis. We identified Bid and 14-3-3 proteins as cytosolic targets of cathepsin D in human fibroblasts. Truncated Bid, generated by cathepsin D proteolytic cleavage, stimulates Bax-mediated release of pro-apoptotic factors from the mitochondria, thereby engaging the intrinsic pathway to apoptosis.

    Since the presence of cathepsins in the cytosol is sufficient to induce apoptosis, the permeability of the lysosomal membrane influences the fate of the cell. In this thesis, we demonstrated that the stability of the lysosomal membrane can be manipulated by altering the lysosomal cholesterol content. Cells with high lysosomal cholesterol content were less prone to undergo apoptosis when challenged with stimuli known to induce lysosome-mediated cell death. In addition, cholesterol accumulation was associated with increased expression of lysosome-associated membrane proteins and storage of other lipids; however, these factors did not contribute to lysosomal stabilization.

    Lysosomal membrane permeabilization and cathepsins contribute to ultraviolet (UV) irradiation-induced apoptosis. We demonstrate plasma membrane damage induced by UVA irradiation to be rapidly repaired by lysosomal exocytosis in human keratinocytes. Despite efficient plasma membrane resealing, the cells underwent apoptosis, which was dependent on early activation of caspase-8. The activation of caspase-8 was lysosome-dependent and occurred in vesicles positive for lysosomal markers.

    This thesis demonstrates the importance of lysosomal stability for apoptosis regulation and that this stability can be influenced by drug intervention. Modulation of the lysosomal membrane permeability may have potential for use as a therapeutic strategy in conditions associated with accelerated or repressed apoptosis.

    Delarbeid
    1. Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe183
    Åpne denne publikasjonen i ny fane eller vindu >>Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe183
    Vise andre…
    2012 (engelsk)Inngår i: Annals of Clinical and Laboratory Science, ISSN 0091-7370, E-ISSN 1550-8080, Vol. 42, nr 3, s. 231-242Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Bax-mediated permeabilization of the outer mitochondrial membrane and release of apoptogenic factors into the cytosol are key events that occur during apoptosis. Likewise, apoptosis is associated with permeabilization of the lysosomal membrane and release of lysosomal cathepsins into the cytosol. This report identifies proteolytically active cathepsin D as an important component of apoptotic signaling following lysosomal membrane permeabilization in fibroblasts. Lysosome-mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Box activator Bid, and translocation of Box to mitochondria, all of which were cathepsin D-dependent. Processing of Bid could be reproduced by enforced lysosomal membrane permeabilization, using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). We identified three cathepsin D-specific cleavage sites in Bid, Phe24, Trp48, and Phe183. Cathepsin D-cleaved Bid induced Bax-mediated release of cytochrome c from purified mitochondria, indicating that the fragments generated are functionally active. Moreover, apoptosis was associated with cytosolic acidification, thereby providing a more favorable environment for the cathepsin D-mediated cleavage of Bid. Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid.

    sted, utgiver, år, opplag, sider
    Institute for Clinical Science, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-80794 (URN)000307091500001 ()
    Merknad

    Funding Agencies|Swedish Cancer Society||Swedish Research Council||Swedish Society for Medical Research||County Council of Ostergotland||foundation of Lars Hierta||foundation of Tore Nilson||foundation of Magn||foundation of Bergvall||foundation of Stohne||foundation of Hedberg||

    The original title of this article in Manuscript was: Cathepsin D-specific processing of Bid at Phe24, Trp48, and Phe183

    Tilgjengelig fra: 2012-08-30 Laget: 2012-08-30 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    2. Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation
    Åpne denne publikasjonen i ny fane eller vindu >>Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation
    Vise andre…
    2011 (engelsk)Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, nr 2, s. 629-639Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

    sted, utgiver, år, opplag, sider
    American Society for Investigative Pathology (ASIP), 2011
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-66151 (URN)10.1016/j.ajpath.2010.10.030 (DOI)000287264400018 ()
    Tilgjengelig fra: 2011-03-04 Laget: 2011-03-04 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    3. Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content
    Åpne denne publikasjonen i ny fane eller vindu >>Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content
    Vise andre…
    2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 11Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-85004 (URN)10.1371/journal.pone.0050262 (DOI)000311885300096 ()23166840 (PubMedID)
    Merknad

    Funding Agencies|Swedish Research Council|2010-3463|Deutsche Forschungsgemeinschaft||foundation of Olle Engqvist||foundation of Ake Wiberg||

    Tilgjengelig fra: 2012-10-30 Laget: 2012-10-30 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes
    Åpne denne publikasjonen i ny fane eller vindu >>Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes
    Vise andre…
    2013 (engelsk)Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, nr 24, s. 5578-5584Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Ultraviolet (UV) irradiation is a major environmental carcinogen involved in the development of skin cancer. To elucidate the initial signaling during UV-induced damage in human keratinocytes, we investigated lysosomal exocytosis and apoptosis induction. UVA, but not UVB, induced plasma membrane damage, which was repaired by Ca2+-dependent lysosomal exocytosis. The lysosomal exocytosis resulted in extracellular release of cathepsin D and acid sphingomyelinase (aSMase). Two hours after UVA irradiation, we detected activation of caspase-8, which was reduced by addition of anti-aSMAse. Furthermore, caspase-8 activation and apoptosis was reduced by prevention of endocytosis and by the use of cathepsin inhibitors. We conclude that lysosomal exocytosis is part of the keratinocyte response to UVA and is followed by cathepsin-dependent activation of caspase-8. The findings have implications for the understanding of UV-induced skin damage and emphasize that UVA and UVB initiate apoptosis through different signaling pathways in keratinocytes.

    sted, utgiver, år, opplag, sider
    Company of Biologists, 2013
    Emneord
    Keratinocyte; UV irradiation; Lysosome; Cathepsin; Endocytosis; Apoptosis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-103290 (URN)10.1242/jcs.130633 (DOI)000328686600005 ()
    Merknad

    The previous status of this article was manuscript with the title Lysosomal exocytosis repairs the plasma membrane after UVA and is followed by caspase-8 induced apoptosis.

    Tilgjengelig fra: 2014-01-17 Laget: 2014-01-16 Sist oppdatert: 2017-08-30
  • 6.
    Appelqvist, Hanna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Linderoth, Emma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Johansson, Uno
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Antonsson, Bruno
    Geneva Research Centre, Switzerland .
    Steinfeld, Robert
    University of Medical Centre Gottingen, Germany .
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe1832012Inngår i: Annals of Clinical and Laboratory Science, ISSN 0091-7370, E-ISSN 1550-8080, Vol. 42, nr 3, s. 231-242Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bax-mediated permeabilization of the outer mitochondrial membrane and release of apoptogenic factors into the cytosol are key events that occur during apoptosis. Likewise, apoptosis is associated with permeabilization of the lysosomal membrane and release of lysosomal cathepsins into the cytosol. This report identifies proteolytically active cathepsin D as an important component of apoptotic signaling following lysosomal membrane permeabilization in fibroblasts. Lysosome-mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Box activator Bid, and translocation of Box to mitochondria, all of which were cathepsin D-dependent. Processing of Bid could be reproduced by enforced lysosomal membrane permeabilization, using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). We identified three cathepsin D-specific cleavage sites in Bid, Phe24, Trp48, and Phe183. Cathepsin D-cleaved Bid induced Bax-mediated release of cytochrome c from purified mitochondria, indicating that the fragments generated are functionally active. Moreover, apoptosis was associated with cytosolic acidification, thereby providing a more favorable environment for the cathepsin D-mediated cleavage of Bid. Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid.

  • 7.
    Appelqvist, Hanna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Cathrine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Garner, Brett
    University of Wollongong.
    Brown, Andrew J
    University of New South Wales.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation2011Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, nr 2, s. 629-639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

  • 8.
    Appelqvist, Hanna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Björnström, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Anestesiologi med intensivvård. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Intensivvårdskliniken US.
    Saftig, Paul
    Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
    Garner, Brett
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

  • 9.
    Bivik, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Rosdahl, Inger
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Hsp70 protects against UVB induced apoptosis by preventing release of cathepsins and cytochrome c in human melanocytes2007Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 28, nr 3, s. 537-544Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stress-induced heat shock protein 70 (Hsp70) effectively protects cells against apoptosis, although the anti-apoptotic mechanism is still undefined. Exposure of human melanocytes to heat and subsequent UVB irradiation increased the level of Hsp70 and pre-heating reduced UVB induced apoptosis. Immunofluorescence staining of Hsp70 in combination with staining of lysosomes (Lamp2) or mitochondria (Mitotracker®) in pre-heated UVB exposed cells showed co-localization of Hsp70 with both lysosomes and mitochondria in the surviving cell population. Furthermore, UVB induced apoptosis was accompanied by lysosomal and mitochondrial membrane permeabilization, detected as release of cathepsin D and cytochrome c, respectively, which were prevented by heat pre-treatment. In purified fractions of lysosomes and mitochondria, recombinant Hsp70 attached to both lysosomal and mitochondrial membranes. Moreover, in apoptotic cells Bax was translocated from a diffuse cytosolic location into punctate mitochondrial-like structures, which was inhibited by Hsp70 induction. Such inhibition of Bax translocation was abolished by transfection with Hsp70 siRNA. Furthermore, Hsp70 siRNA eliminated the apoptosis preventive effect observed after pre-heating. These findings show Hsp70 to rescue melanocytes from UVB induced apoptosis by preventing release of cathepsins from lysosomes, Bax translocation and cytochrome c release from mitochondria.

     

    Abbreviations: AIF, apoptosis-inducing factor; Hsp, heat shock protein; NAG, ß-N-acetylglucosaminidase; tBid, truncated Bid; UV, ultraviolet

  • 10.
    Bivik, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Wäster, Petra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Rosdahl, Inger
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    UVA/B induced apoptosis in human melanocytes involves translocation of cathepsins and Bcl-2 family members2006Inngår i: Journal of Investigative Dermatology, ISSN 0022-202X, Vol. 126, nr 5, s. 1119-1127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We demonstrate UVA/B to induce apoptosis in human melanocytes through the mitochondrial pathway, displaying cytochrome c release, caspase-3 activation, and fragmentation of nuclei. The outcome of a death signal depends on the balance between positive and negative apoptotic regulators, such as members of the Bcl-2 protein family. Apoptotic melanocytes, containing fragmented nucleus, show translocation of the proapoptotic proteins Bax and Bid from the cytosol to punctate mitochondrial-like structures. Bcl-2, generally thought to be attached only to membranes, was in melanocytes localized in the cytosol as well. In the fraction of surviving melanocytes, that is, cells with morphologically unchanged nucleus, the antiapoptotic proteins Bcl-2 and Bcl-XL were translocated to mitochondria following UVA/B. The lysosomal proteases, cathepsin B and D, which may act as proapoptotic mediators, were released from lysosomes to the cytosol after UVA/B exposure. Proapoptotic action of the cytosolic cathepsins was confirmed by microinjection of cathepsin B, which induced nuclear fragmentation. Bax translocation and apoptosis were markedly reduced in melanocytes after pretreatment with either cysteine or aspartic cathepsin inhibitors. No initial caspase-8 activity was detected, excluding involvement of the death receptor pathway. Altogether, our results emphasize translocation of Bcl-2 family proteins to have central regulatory functions of UV-induced apoptosis in melanocytes and suggest cathepsins to be proapoptotic mediators operating upstream of Bax.

  • 11.
    Bivik, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    JNK mediates UVB-induced apoptosis upstream lysosomal membrane permeabilization and Bcl-2 family proteins2008Inngår i: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 13, nr 9, s. 1111-1120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    UVB irradiation induced phosphorylation of JNK and subsequent apoptosis in human melanocytes. Depletion of both JNK1 and JNK2 expression using siRNA transfection, protected against apoptosis, as detected by decreased nuclear fragmentation and caspase-3 activity, as well as reduced translocation of Bax to mitochondria. Moreover, release of cathepsin B and D from lysosomes to the cytosol was reduced when JNK expression was suppressed by siRNA, demonstrating a JNK dependent regulation of lysosomal membrane permeabilization. In unirradiated control melanocytes, coimmunoprecipitation showed that Bim was sequestered by Mcl-1, which had a pro-survival function. After UVB irradiation, a significant decrease in Mcl-1 protein level was found, which was prevented by addition of a proteasome inhibitor. The interaction between Bim and Mcl-1 was reduced in response to UVB irradiation and Bim was phosphorylated in a JNK dependent manner. In conclusion, these findings Suggest JNK to have an important pro-apoptotic function following UVB irradiation in human melanocytes, by acting upstream of lysosomal membrane permeabilization and Bim phosphorylation.

  • 12.
    Bjartmar, Lisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Alkhori, Liza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ruud, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Geriatriska kliniken.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi.
    Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula2010Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, s. 24-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

  • 13.
    Borch, Kurt
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Skarsgard, J
    Franzén, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Mårdh, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Rehfeld, JF
    Benign gastric polyps - Morphological and functional origin2003Inngår i: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 48, nr 7, s. 1292-1297Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The most common types of benign gastric polyps are fundic gland polyps, hyperplastic polyps, and adenomas. The aim of this study was to determine on which morphological and functional background benign gastric polyps develop. The study includes 85 consecutive patients with gastric polyps and sex and age-matched controls without polyps selected at random from a general population sample. The type of polyp was hyperplastic in 52 (61%), fundic gland in 18 (21%), adenoma in 10 (12%), carcinoid in 2 (2%), hamartoma in 2 ( 2%), and inflammatory fibroid in 1 (1%) of the cases. Routine biopsies from the gastric corpus and antrum were examined for presence of gastritis and H. pylori. Blood samples were analyzed for H. pylori antibodies, H+, K+-ATPase antibodies, gastrin, and pepsinogen I. Patients with hyperplastic polyps had increased P-gastrin concentrations and S-H+, K+-ATPase antibody titers and decreased S-pepsinogen I concentrations with a high prevalence of atrophic corpus gastritis or pangastritis. A similar pattern was observed among patients with adenomas, whereas patients with fundic gland polyps had normal serology and a lower prevalence of gastritis and H. pylori infection than controls. In conclusion, hyperplastic polyps and adenomas are generally associated with atrophic gastritis. Patients with fundic gland polyps seem to have a sounder mucosa than controls. Whereas the risk of malignant gastric neoplasia is increased in patients with hyperplastic polyps or adenomas, this does not seem to be the case in patients with fundic gland polyps.

  • 14.
    Brunk, Ulf
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Yu, ZQ
    Persson, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Lungmedicinska kliniken US.
    Eaton, John Wallace
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Lysosomes, iron and oxidative stress2003Inngår i: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 37, s. 34-34Konferansepaper (Annet vitenskapelig)
  • 15.
    Danielsson, Olof
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Neurologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Cathrine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Lindvall, Bjorn
    University Hospital Örebro.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle2009Inngår i: NEUROMUSCULAR DISORDERS, ISSN 0960-8966, Vol. 19, nr 6, s. 412-417Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

  • 16.
    Elander, Louise
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Prostaglandin E2 receptors in IL-1β induced anorexiaManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Anorexia in response to immune challenge by Interleukin-1β (IL-1β) has been shown to be dependent on Prostaglandin E2 (PGE2) produced by the inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1). However, it is not known which of the four known PGE2 receptors EP1-4, encoded by the genes Ptger 1-4, that mediates the PGE2-induced anorexia. Here we examined food intake in mice deficient in EP1, EP2 and EP3, respectively, during normal conditions and following treatment with IL-1β. Neither of the gene deletions affected baseline food intake, and all the three genotypes displayed anorexia following IL-1β injection, similar to wild type mice. Previous work has demonstrated that the EP3 receptor is critical for the generation of fever, and that EP1 and EP3 receptors mediate inflammationinduced activation of the hypothalamic-pituitary-adrenal (HPA) axis. The present data, showing intact anorexigenic responses in EP1 and EP3 deficient mice, as well as in mice with deletion of the EP2 receptor, hence suggest that PGE2-elicited acute phase responses are mediated by distinct set or sets of PGE2-receptors.

  • 17.
    Eriksson, Ida
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Joosten, M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    The histone deacetylase inhibitor trichostatin A reduces lysosomal pH and enhances cisplatin-induced apoptosis2013Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, nr 1, s. 12-20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High activity of histone deacetylases (HDACs) has been documented in several types of cancer and may be associated with survival advantage. In a head and neck squamous cell carcinoma cell line, cisplatin-induced apoptosis was augmented by pretreatment with the HDAC inhibitor trichostatin Apoptosis was accompanied by lysosomal membrane permeabilization (LMP), as shown by immunoblotting of the lysosomal marker protease cathepsin B in extracted cytosol and by immunofluorescence. Moreover, LAMP-2 (lysosomal associated membrane protein-2) was translocated from lysosomal membranes and found in a digitonin extractable fraction together with cytosolic proteins and pretreatment with trichostatin A potentiated the release. Overall, protein level of LAMP-2 was decreased during cell death and, interestingly, inhibition of cysteine cathepsins, by the pan-cysteine cathepsin inhibitor zFA-FMK, prevented loss of LAMP-2. The importance of LAMP-2 for lysosomal membrane stability, was confirmed by showing that LAMP-2 knockout MEFs (mouse embryonic fibroblasts) were more sensitive to cisplatin as compared to the corresponding wildtype cells. Trichostatin A reduced lysosomal pH from 4.46 to 4.25 and cell death was prevented when lysosomal pH was increased by NH4Cl, or when inhibiting the activity of lysosomal proteases. We conclude that trichostatin A enhances cisplatin induced cell death by decreasing lysosomal pH, which augments cathepsin activity resulting in reduced LAMP-2 level, and might promote LMP.

  • 18.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Jedlinski, Adam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Vainikka, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Grenman, Reidar
    University of Turku.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines2009Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 24, nr 4, s. 549-556Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearsons correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p andlt;= 0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3(241) and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p andlt;= 0.001).

  • 19.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Ceder, Rebecca
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland C
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Vainikka, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Grénman, Reidar
    Medical Biochemistry, University of Turku, Finland.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines2011Inngår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, nr 10, s. 739-746Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

    METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

    RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

    CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

  • 20.
    Frennesson, Christina
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Larsson, R
    Hultman, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Nilsson, SG
    Drusen and choroidal neovascularization (CNV) in patients with dense deposit disease (membrano-proliferative glomerulonephritis type II). Favourable effect of photodynamic treatment (PDT)2003Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 44, s. 1774-Konferansepaper (Annet vitenskapelig)
  • 21.
    Gao, Jingfang
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Knutsen Holmqvist, Annica
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Franlund, B
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer2009Inngår i: DIGESTIVE AND LIVER DISEASE, ISSN 1590-8658, Vol. 41, nr 2, s. 116-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose. The aim of this study was to get a deeper understanding into how adults with cerebral palsy (CP) experience physiotherapy and physical activity in a perspective from childhood to adulthood; and how personal and environmental factors influence possibilities for physiotherapy and physical activity. Method. Data was collected through interviews with 22 community-living adults (35-68 years) with CP, from five counties in Sweden. The questions were open-ended and the interviews were taped and transcribed to written language. The material was analysed through qualitative content analysis, a classification process resulting in different themes. Results. The narratives from the 22 informants, based on experiences from childhood to adulthood, resulted in a description of prerequisites for carrying out physiotherapy and physical activity. Five different themes were identified: (i) Being enjoyable, (ii) Giving effects, (iii) Being comprehensible, (iv) Being integrated in daily life, and (v) Supportive healthcare with competent professionals. Conclusion. The information from the interviews elucidates the importance of a lifelong support from healthcare professionals. Physiotherapists with attentiveness to different life situations in combination with good understanding and knowledge in CP could facilitate continuous physical activity in people growing up and ageing with CP.

  • 22.
    Gao, X.
    et al.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Oncology, Institute of Biomedicine and Surgery, University of Linköping, Linköping, 58185, Sweden.
    Qian, M.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States.
    Campian, J.L.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States.
    Clark, D.R.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States.
    Burke, T.J.
    Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States.
    Eaton, John Wallace
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    McGregor, W.G.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40202, United States.
    Cytotoxic and mutagenic effects of tobacco-borne free fatty acids2006Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 40, nr 1, s. 165-172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tobacco smoke contains substances capable of binding iron in an aqueous medium and transferring the metal into both organic solvents and intact mammalian red cells. This iron-binding activity is due to free fatty acids which are abundant in tobacco smoke and form 2:1 (free fatty acid:iron) chelates with ferrous iron. These earlier observations suggested that smoke-borne free fatty acids and the associated delocalization of iron within the lung might contribute to both the chronic pulmonary inflammation and the carcinogenesis associated with smoking. We now report that micromolar concentrations of iron or free fatty acid are not toxic to cultured human lung fibroblasts. However, when combined, the same low concentrations of iron and free fatty acid exert synergistic toxicity. Furthermore, the combination of free fatty acid and iron is highly mutagenic, inducing almost as many selectable mutations in the gene for hypoxanthine/guanine phosphoribosyl transferase as does benzo[a] pyrenediolepoxide, a class I carcinogen generated from benzo[a]pyrene present in cigarette smoke. The combination of free fatty acid and iron also promotes transformation of NIH 3T3 cells into an anchorage-independent phenotype. We conclude that free fatty acids in tobacco smoke may be important contributors to both the pulmonary damage and the carcinogenesis associated with smoking. © 2005 Elsevier Inc. All rights reserved.

  • 23.
    Gao, Xueshan
    et al.
    University of Louisville.
    Li Campian, Jian
    University of Louisville.
    Qian, Mingwei
    University of Louisville.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wallace Eaton, John
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Mitochondrial DNA Damage in Iron Overload2009Inngår i: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 284, nr 8, s. 4767-4775Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic iron overload has slow and insidious effects on heart, liver, and other organs. Because iron-driven oxidation of most biologic materials (such as lipids and proteins) is readily repaired, this slow progression of organ damage implies some kind of biological "memory." We hypothesized that cumulative iron-catalyzed oxidant damage to mtDNA might occur in iron overload, perhaps explaining the often lethal cardiac dysfunction. Real time PCR was used to examine the " intactness" of mttDNA in cultured H9c2 rat cardiac myocytes. After 3 -5 days exposure to high iron, these cells exhibited damage to mtDNA reflected by diminished amounts of near full-length 15.9-kb PCR product with no change in the amounts of a 16.1-kb product from a nuclear gene. With the loss of intact mtDNA, cellular respiration declined and mRNAs for three electron transport chain subunits and 16 S rRNA encoded by mtDNA decreased, whereas no decrements were found in four subunits encoded by nuclear DNA. To examine the importance of the interactions of iron with metabolically generated reactive oxygen species, we compared the toxic effects of iron in wild-type and rhoo cells. In wild-type cells, elevated iron caused increased production of reactive oxygen species, cytostasis, and cell death, whereas the rhoo cells were unaffected. We conclude that long-term damage to cells and organs in iron-overload disorders involves interactions between iron and mitochondrial reactive oxygen species resulting in cumulative damage to mtDNA, impaired synthesis of respiratory chain subunits, and respiratory dysfunction.

  • 24.
    Gati, Istvan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi. Linköpings universitet, Hälsouniversitetet.
    Danielsson, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi. Linköpings universitet, Hälsouniversitetet.
    Betmark, T.
    Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Dizdar (Dizdar Segrell), Nil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Culturing of diagnostic muscle biopsies as spheroid-like structures: a pilot study of morphology and viability2010Inngår i: Neurological Research, ISSN 0161-6412, E-ISSN 1743-1328, Vol. 32, nr 6, s. 650-655Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The aim of this study was to establish three-dimensional cultures originating from muscle biopsies and evaluate the viability and morphology. Method: Muscle biopsies from patients with suspected neuromuscular disorders were obtained and established as primary muscle tissue cultures. Tissue pieces, 1-2 mm of diameters, were placed in culture medium and subjected to sporadic stirring to prevent attachment and outgrowth as monolayer cells. Morphology and ability to attach to the surface were investigated by light microscopy. Viability was evaluated by Tc-99m-tetrofosmin uptake. After 1 month, histology was evaluated by light microscopy and immunocytochemistry. The findings of a healthy muscle and a dystrophic muscle were compared. Results: Initially, the tissue pieces were unshaped but formed spheroid-like structures during the culture period. For dystrophic muscle, attachment capacity to the surface was initially potent and decreased during the culture period, whereas control muscle showed weak attachment from the start that increased during the culture period. The uptake of Tc-99m-tetrofosmin increased in control muscle, while it decreased in dystrophic muscle, during the culture period. The histological investigation demonstrated larger destruction of myofiber, weaker satellite cell activation and reduced myofiber regeneration in the dystrophic muscle as compared to the control muscle. Conclusion: The cellular components of the muscle tissue can survive and proliferate as spheroid-like primary cultures. The cellular composition resembles the in vivo condition, which allows studies of degeneration of the original fibers, and activation and proliferation of the satellite cells. The culture system may provide better understanding of the degeneration and regeneration processes in different muscle disorders and allow investigations of pharmacological interventions.

  • 25.
    Ghosh, Moumita
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Laskar, Amit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Yuan, XiMing
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Li, Wei
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages2011Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, nr 4, s. 623-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Moderate lysosomal membrane permeabilization (LMP) is an important inducer of apoptosis. Macrophages are professional scavengers and are rich in hydrolytic enzymes and iron. In the present study, we found that LMP by lysosomotropic detergent MSDH resulted in early up-regulation of lysosomal cathepsins, oxidative stress and ferritin up-regulation, and cell death. Lysosomotropic base NH(4)Cl reduced the ferritin induction and oxidative stress in apoptotic cells induced by MSDH. Cysteine cathepsin inhibitors significantly protected cell death and oxidative stress, but had less effect on ferritin induction. We conclude that oxidative stress induced by lysosomal rupture causes ferritin induction with concomitant mitochondrial damage, which are the potential target for prevention of cellular oxidative stress and cell death induced by typical lysosomotropic substances in different disorders.

  • 26.
    Gréen,, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lönn, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Holmgren Peterson, Kajsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Rundquist, Ingemar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Translocation of Histone H1 Subtypes Between Chromatin and Cytoplasm During Mitosis in Normal Human Fibroblasts2010Inngår i: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 77A, nr 5, s. 478-484Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Histone H1 is an important constituent of chromatin which undergoes major structural rearrangements during mitosis. However, the role of H1, multiple H1 subtypes and H1 phosphorylation is still unclear. In normal human fibroblasts, phosphorylated H1 was found located in nuclei during prophase and in both cytoplasm and condensed chromosomes during metaphase, anaphase and telophase as detected by immunocytochemistry. Moreover, we detected remarkable differences in the distribution of the histone H1 subtypes H1.2, H1.3 and H1.5 during mitosis. H1.2 was found in chromatin during prophase, and almost solely in the cytoplasm of metaphase and early anaphase cells. In late anaphase it appeared in both chromatin and cytoplasm, and again in chromatin during telophase. H1.5 distribution pattern resembled that of H1.2, but some H1.5 remained situated in chromatin during metaphase and early anaphase. H1.3 was detected in chromatin in all cell cycle phases. We propose therefore, that H1 subtype translocation during mitosis is controlled by phosphorylation, in combination with H1 subtype inherent affinity. We conclude that H1 subtypes, or their phosphorylated variants, may be signalling molecules in mitosis or that they leave chromatin in a regulated way to give access for chromatin condensing factors or transcriptional regulators during mitosis.

  • 27.
    Gudjonsson, Sigurdur
    et al.
    Skåne University Hospital, Sweden .
    Blackberg, Mats
    Helsingborg County Hospital, Sweden .
    Chebil, Gunilla
    Helsingborg County Hospital, Sweden .
    Jahnson, Staffan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Olsson, Hans
    Lund University, Sweden .
    Bendahl, Par-Ola
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Mansson, Wiking
    Skåne University Hospital, Sweden .
    Liedberg, Fredrik
    Skåne University Hospital, Sweden Vaxjo County Hospital, Sweden .
    The value of bladder mapping and prostatic urethra biopsies for detection of carcinoma in situ (CIS)2012Inngår i: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 110, nr 2B, s. E41-E45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES To assess the value of bladder mapping and prostatic urethra biopsies for detection of urothelial carcinoma in situ (CIS). CIS of the urinary bladder is a flat high-grade lesion of the mucosa associated with a significant risk of progression to muscle-invasive disease. CIS is difficult to identify on cystoscopy, and definite diagnosis requires histopathology. Traditionally, if CIS is suspected, multiple cold-cup biopsies are taken from the bladder mucosa, and resection biopsies are obtained from the prostatic urethra in males. This approach is often called bladder mapping (BMAP). The accuracy of BMAP as a diagnostic tool is not known. PATIENTS AND METHODS Male patients with bladder cancer scheduled for cystectomy underwent cold-cup bladder biopsies (sidewalls, posterior wall, dome, trigone), and resection biopsies were taken from the prostatic urethra. After cystectomy, the surgical specimen was investigated in a standardised manner and subsequently compared with the BMAP biopsies for the presence of CIS. RESULTS The histopathology reports of 162 patients were analysed. CIS was detected in 46% of the cystoprostatectomy specimens, and multiple (greater than= 2) CIS lesions were found in 30%. BMAP (cold-cup bladder biopsies + resection biopsies from the prostatic urethra) provided sensitivity of 51% for any CIS, and 55% for multiple CIS lesions. The cold-cup biopsies for CIS in the bladder mucosa showed sensitivity and specificity of 46% and 89%, respectively. CONCLUSION Traditional cold-cup biopsies are unreliable for detecting CIS in bladder mucosa and negative findings must be interpreted with caution.

  • 28.
    Göransson, Anna-Lena
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Kanmert, Daniel
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Nilsson, K. Peter R.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants2012Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, nr 4, s. 895-900Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer’s disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

  • 29.
    Haj-Hosseini, Neda
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Tekniska högskolan.
    Richter, Johan
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Neurokirurgiska kliniken US.
    Olivecrona, Magnus
    Department of Neurosurgery, Umeå University.
    Hillman, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurokirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Neurokirurgiska kliniken US.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Wårdell, Karin
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Tekniska högskolan.
    Fluorescence guided spectroscopy versus fluorescence microscopy for brain tumor resection2013Konferansepaper (Annet vitenskapelig)
  • 30.
    Hamzic, Namik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tang, Yanjuan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ruud, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nilsberth, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Interleukin-6 produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile responseManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoetic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 in the cerebrospinal fluid (CSF) and in plasma as well as similar expression of the IL-6 gene in the brain as WT mice. In contrast, IL-6 KO mice, with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of nonhematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

  • 31.
    Han, Yang
    et al.
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Zhang, Yong
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Yang, Lian-he
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Mi, Xiao-yi
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Dai, Shun-dong
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Li, Qing-chang
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Xu, Hong-tao
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Yu, Juan-han
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    Li, Guang
    First Affiliated Hospital of China Medical University, Shenyang, China.
    Zhao, Jing
    First Affiliated Hospital of China Medical University, Shenyang, China.
    Han, Chong
    First Affiliated Hospital of China Medical University, Shenyang, China.
    Yuan, Xi-ming
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    Wang, En-hua
    College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, China.
    X-radiation inhibits histone deacetylase 1 and 2, upregulates Axin expression and induces apoptosis in non-small cell lung cancer2012Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 7, nr 183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Histone deacetylase (HDAC) plays an important role in the deacetylation of histone, which can alter gene expression patterns and affect cell behavior associated with malignant transformation. The aims of this study were to investigate the relationships between HDAC1, HDAC2, clinicopathologic characteristics, patient prognosis and apoptosis, to clarify the mechanism of upregulation of the Axis inhibitor Axin (an important regulator of the Wnt pathway) by X-radiation and to elucidate the effect of siRNA on radiation therapy of non-small cell lung cancer (NSCLC).

    Methods

    HDAC1 and HDAC2 expression levels were measured by immunohistochemistry and reverse transcription PCR. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling and fluorescence activated cell sorting. BE1 cells expressing Axin were exposed to 2 Gy of X-radiation.

    Results

    Expression of HDAC1 and that of HDAC2 were correlated, and significantly higher in NSCLC tissues than in normal lung tissues (P < 0.05). HDAC1 and HDAC2 expression was correlated with pTNM stage and negatively correlated with differentiation of NSCLC and apoptotic index (P < 0.05). The prognosis of patients with low expression of HDAC1 and HDAC2 was better than that of those with high expression. X-radiation and siRNA inhibited HDAC1 and HDAC2 expression in NSCLC cells and Axin levels were significantly higher in BE1 cells.

    Conclusions

    X-radiation and siRNA inhibit expression of HDAC1 and HDAC2, weaken the inhibitory effect of HDAC on Axin, upregulate Axin expression and induce apoptosis of lung cancer cells. Inhibition of HDAC1 and HDAC2 is a means of enhancing the radiosensitivity of NSCLC.

  • 32.
    Havarinasab, Said
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi.
    Hultman, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Organic mercury compounds and autoimmunity2005Inngår i: Autoimmunity Reviews, ISSN 1568-9972, E-ISSN 1873-0183, Vol. 4, nr 5, s. 270-275Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Based on in vitro studies and short-term in vivo studies, all mercurials were for a long time considered as prototypic immunosuppressive substances. Recent studies have confirmed that organic mercurials such as methyl mercury (MeHg) and ethyl mercury (EtHg) are much more potent immunosuppressors than inorganic mercury (Hg). However, Hg interacts with the immune system in the presence of a susceptible genotype to cause immunostimulation, antinucleolar antibodies targeting fibrillarin, and systemic immune-complex (IC) deposits, a syndrome called Hg-induced autoimmunity (HgIA). Recent studies in mice with a susceptible genotype has revealed that the immunosuppressive effect of MeHg and EtHg will within 1-3 weeks be superseded by immunostimulation causing an HgIA-like syndrome. At equimolar doses of Hg, MeHg has the weakest immunostimulating, autoimmunogen, and IC-inducing effect, while the effect of thimerosal is similar to that of inorganic mercury. The immunosuppression is caused by the organic mercurials per se. Since they undergo rapid transformation to inorganic Hg, studies are being undertaken to delineate the importance of the organic substances per se and the newly formed inorganic Hg for induction of autoimmunity. © 2004 Elsevier B.V. All rights reserved.

  • 33.
    Hoem, D.
    et al.
    Department of Surgery, Institute of Surgical Sciences, Haukeland University Hospital, Bergen, Norway, Department of Surgery, Haukeland University Hospital, NO-5021 Bergen, Norway.
    Hostmark, J.
    Höstmark, J., Department of Surgery, Institute of Surgical Sciences, Haukeland University Hospital, Bergen, Norway.
    Dalen, Helge
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Andren-Sandberg, A.
    Andrén-Sandberg, Å., Department of Surgery, Institute of Surgical Sciences, Haukeland University Hospital, Bergen, Norway.
    Non-adhesive organ culture of human biliary epithelium with stroma2008Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 43, nr 4, s. 473-479Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. Explanted tissue has been shown to keep adult human cells in organ culture with a preserved morphology for at least one month as spheres in a non-adhesive organ culture. In the present study, we explored whether also human biliary epithelium can be grown in this manner, because the result may be of interest in studies of hepato-biliary-pancreatic carciogenesis. Material and methods. Small tissue samples were obtained from the gallbladder wall of patients who had been operated upon with cholecystectomy. Fragments of about 300 µm in diameter from each patient were cultured and investigated with light microscopy at the time of explantation and after 5, 10, 20, 30 and 40 days of culture. Scanning and transmission electron microscopy were performed to demonstrate the ultrastructure. Incubation of cultured fragments with the vital dyes revealed a viable epithelium. Results. At the time of explantation, all the tissue fragments had a rough appearance with an uneven, torn periphery, while during the first few days of culture they became rounder with a smooth-looking surface covering the entire circumference. This spheroid morphology persisted for the remainder of the culture period. The core of the fragments harboured connective tissue with vascular elements, fibroblasts and leucocytes. Immunostaining for cytokeratin 7, 19 and 20 revealed a strong positive staining of the epithelium. Conclusions. These results show that biliary epithelium can be grown in vitro in a non-adhesive organ culture with their stroma. © 2008 Taylor & Francis.

  • 34.
    Hultman, Per
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Taylor, A.
    Department of Molecular and Experimental Medicine, Scripps Research Institute, San Diego, CA, United States.
    Yang, J.M.
    Department of Molecular and Experimental Medicine, Scripps Research Institute, San Diego, CA, United States.
    Pollard, K.M.
    Department of Molecular and Experimental Medicine, Scripps Research Institute, San Diego, CA, United States.
    The effect of xenobiotic exposure on spontaneous autoimmunity in (SWR x SJL)F1 hybrid mice2006Inngår i: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 69, nr 6, s. 505-523Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    F1 hybrids of SWR (H-2q) and SJL (H-2s) mice spontaneously develop a lupuslike condition in an age-dependent manner, and these two H-2 haplotypes also confer susceptibility to induction of systemic autoimmunity by heavy metals such as mercury, silver, and gold with antifibrillarin antibodies (AFA) as marker. The aim of this study was to determine how the mixing of two susceptible genomes might influence expression of idiopathic and induced autoimmunity over a period of 14 mo of exposure to mercury and silver. Spontaneous autoimmunity first appeared as antinuclear antibodies (ANA) in females at 10 wk of age and in males at 10 mo of age, and was followed by development of anti-chromatin antibodies. Antibodies to double-stranded DNA developed in 60% of males and 20% of females. Thirty percent of males and 10% of females developed a coarsely speckled ANA pattern associated with high titers of anti-Sm antibodies. Glomerular immune complex (IC) deposits and a proliferative glomerulonephritis were seen at 17 mo of age. The F1 hybrids treated with metals showed no exaggeration of spontaneous autoimmunity. However, the metals suppressed the spontaneous development of anti-Sm and antichromatin antibodies. The metal-induced AFA, linked to the H-2s and H-2q haplotype, reached a maximum after 3-4 mo of treatment and then declined, 33% of the silver-treated hybrids finally became AFA-negative, despite continuous treatment. The decline in ANoA during metal treatment is contrary to the situation in metal-treated SJL mice. This indicates that dominant SWR background genes suppressed induction of certain autoimmune traits in the (SWR x SJL)F1 hybrid mice. Copyright© Taylor & Francis Group, LLC.

  • 35.
    Jedlinski, Adam
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    EGFR status and EGFR ligand expression influence the treatment response of head and neck cancer cell lines2013Inngår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 42, nr 1, s. 26-36Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Combination treatment (chemoradiotherapy) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems. A high level of epidermal growth factor receptor (EGFR) has been associated with a more aggressive phenotype as well as decreased responsiveness to radio- or chemotherapy. We examined the role of EGFR status and EGFR ligand expression for the treatment response. Methods: Intrinsic sensitivity to radiotherapy, cisplatin, and cetuximab treatments was investigated in 25 HNSCC cell lines. EGFR gene copy number, mRNA and protein expression, EGFR and Akt phosphorylation status, and mRNA expression of the EGFR ligands were analyzed using quantitative PCR and ELISA and assessed for their impact on treatment sensitivity. Results: Different treatment modalities yielded great diversity in outcome; of note, cetuximab treatment stimulated growth in one cell line. When treatments were combined primarily additive effects were observed. While radioresistance tended to be associated with a high level of phosphorylated EGFR (pEGFR; P = 0.09), cetuximab-resistant cells had low levels of pEGFR (P = 0.13). The three most cetuximab-sensitive cell lines had high EGFR gene copy numbers. Furthermore, cetuximab treatment response was significantly correlated with epiregulin mRNA expression (r = -0.408, P = 0.043). Cisplatin-resistant tumor cells expressed significantly lower levels of EGFR protein (P = 0.04) compared to cisplatin-sensitive cells and tended to have lower levels of phosphorylated Akt (pAkt; P = 0.13) and lower expression levels of amphiregulin (P = 0.18). Conclusions: Epidermal growth factor receptor status and ligand expression influence the treatment sensitivity of HNSCC cells and may be useful as predictive markers.

  • 36.
    Jerhammar, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Welander, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    YAP1 Gene Amplification is a Marker for Cetuximab Resistance in Head and Neck CancerManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is commonly overexpressed in head and neck squamous cell carcinomas (HNSCC). The monoclonal antibody cetuximab (Erbitux®) inhibits its signaling and has been approved for treatment of HNSCC. However, since many patients do not benefit from cetuximab treatment, predictive biomarkers of cetuximab response are required. The present study aims at finding novel markers of cetuximab resistance.

    The intrinsic cetuximab sensitivity of 35 HNSCC cell lines was determined, and revealed a great variation in the response between cell lines. Five cell lines (14%) were cetuximab sensitive, and 12 (34%) were resistant. Interestingly, two cell lines proliferated after cetuximab treatment.

    10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR  verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant.

    YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.

  • 37. Bestill onlineKjøp publikasjonen >>
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomal Membrane Permeabilization: A Cellular Suicide Strategy2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In the last decade, a tremendous gain in knowledge concerning the molecular events of apoptosis signaling and execution has been achieved.

    The aim of this thesis was to clarify the role of lysosomal membrane permeabilization and lysosomal proteases, cathepsins, in signaling for apoptosis. We identified cathepsin D as an important factor in staurosporine-induced human fibroblast cell death. After release to the cytosol, cathepsin D promoted mitochondrial release of cytochrome c by proteolytic activation of Bid. Cathepsin D-mediated cleavage of Bid generated two fragments with the apparent molecular mass of 15 and 19 kDa. By sequence analysis, three cathepsin D-specific cleavage sites, Phe24, Trp48, and Phe183, were identified. Moreover, we investigated the mechanism by which cathepsins escape the lysosomal compartment, and found that Bax is translocated from the cytosol to lysosomes upon staurosporine treatment. In agreement with these data, recombinant Bax triggered release of cathepsins from isolated rat liver lysosomes. Conceivably, the Bcl-2 family of proteins may govern release of pro-apoptotic factors from both lysosomes and mitochondria. The importance of lysosomal cathepsins in apoptosis signaling was studied also in oral squamous cell carcinoma cells following exposure to the redox-cycling drug naphthazarin or agonistic anti-Fas antibodies. In this experimental system, cathepsins were released to the cytosol, however, inhibition of neither cathepsin D, nor cysteine cathepsin activity suppressed cell death. Interestingly, cysteine cathepsins still appeared to be involved in activation of the caspase cascade. Cathepsins are often overexpressed and secreted by cancer cells, and it has been reported that extracellular cathepsins promote tumor growth and metastasis. Here, we propose that cathepsin B secreted from cancer cells may suppress cancer cell death by shedding of the Fas death receptor.

    Defects in the regulation of apoptosis contribute to a wide variety of diseases, such as cancer, neurodegeneration and autoimmunity. Increased knowledge of the molecular details of apoptosis could lead to novel, more effective, treatments for these illnesses. This thesis emphasizes the importance of the lysosomal death pathway, which is a promising target for future therapeutic intervention.

    Delarbeid
    1. Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine
    Åpne denne publikasjonen i ny fane eller vindu >>Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine
    2003 (engelsk)Inngår i: Cell Death and Differentiation, ISSN 1350-9047, Vol. 10, nr 11, s. 1253-1259Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    There is increasing evidence that proteases other than caspases, for example, the lysosomal cathepsins B, D and L, are involved in apoptotic cell death. In the present study, we present data that suggest a role for cathepsin D in staurosporine-induced apoptosis in human foreskin fibroblasts. Cathepsin D and cytochrome c were detected partially released to the cytosol after exposure to 0.1 µM staurosporine for 1 h. After 4 h, activation of caspase-9 and -3 was initiated and later caspase-8 activation and a decrease in full-length Bid were detected. Pretreatment of cells with the cathepsin D inhibitor, pepstatin A, prevented cytochrome c release and caspase activation, and delayed cell death. These results imply that cytosolic cathepsin D is a key mediator in staurosporine-induced apoptosis. Analysis of the relative sequence of apoptotic events indicates that, in this cell type, cathepsin D acts upstream of cytochrome c release and caspase activation.

    Emneord
    apoptosis, caspases, cathepsin D, cytochrome c, fibroblasts, lysosomes
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13200 (URN)10.1038/sj.cdd.4401290 (DOI)
    Tilgjengelig fra: 2008-04-17 Laget: 2008-04-17 Sist oppdatert: 2017-08-30
    2. Lysosomal membrane permeabilization during apoptosis: Involvement of Bax?
    Åpne denne publikasjonen i ny fane eller vindu >>Lysosomal membrane permeabilization during apoptosis: Involvement of Bax?
    Vise andre…
    2005 (engelsk)Inngår i: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 86, nr 5, s. 309-321Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Bcl-2 family members have long been known to control permeabilization of the mitochondrial membrane during apoptosis, but involvement of these proteins in lysosomal membrane permeabilization (LMP) was not considered until recently. The aim of this study was to investigate the mechanism underlying the release of lysosomal proteases to the cytosol seen during apoptosis, with special emphasis on the role of Bax. In human fibroblasts, exposed to the apoptosis-inducing drug staurosporine (STS), the release of the lysosomal protease cathepsin D to the cytosol was observed by immunocytochemistry. In response to STS treatment, there was a shift in Bax immunostaining from a diffuse to a punctate pattern. Confocal microscopy showed co-localization of Bax with both lysosomes and mitochondria in dying cells. Presence of Bax at the lysosomal membrane was confirmed by immuno-electron microscopy. Furthermore, when recombinant Bax was incubated with pure lysosomal fractions, Bax inserted into the lysosomal membrane and induced the release of lysosomal enzymes. Thus, we suggest that Bax is a mediator of LMP, possibly promoting the release of lysosomal enzymes to the cytosol during apoptosis.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2005
    Emneord
    Bax, cathepsins, lysosomes, lysosomal membrane permeabilization, mitochondria
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13201 (URN)10.1111/j.0959-9673.2005.00442.x (DOI)
    Merknad

    The previous status of this article was Manuscript and the working title was Insertion of Bax into lysosomal membranes promotes release of lysosomal proteases during apoptosis.

    Tilgjengelig fra: 2008-04-17 Laget: 2008-04-17 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. Cathepsin D-mediated processing of Bid at Phe24, Trp48, and Phe183
    Åpne denne publikasjonen i ny fane eller vindu >>Cathepsin D-mediated processing of Bid at Phe24, Trp48, and Phe183
    Vise andre…
    2008 (engelsk)Inngår i: International Journal of Experimental PathologyArtikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13202 (URN)
    Tilgjengelig fra: 2008-04-17 Laget: 2008-04-17 Sist oppdatert: 2017-08-30
    4. Role of lysosomal cathepsins in naphthazarin- and Fas-induced apoptosis in oral squamous cell carcinoma cells
    Åpne denne publikasjonen i ny fane eller vindu >>Role of lysosomal cathepsins in naphthazarin- and Fas-induced apoptosis in oral squamous cell carcinoma cells
    2006 (engelsk)Inngår i: Acta Oto-Laryngologica, ISSN 0001-6489, Vol. 126, nr 1, s. 70-81Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Conclusion. Intracellular cysteine cathepsins are pro-apoptotic factors involved in activation of caspases in two oral squamous cell carcinoma (SCC) cell lines.

    Objective. To study the possible involvement of lysosomal cathepsins in oral SCC cell apoptosis.

    Material and methods. Apoptosis was induced in the two human oral SCC cell lines UT-SCC-20A and UT-SCC-24A using naphthazarin or anti-Fas antibodies, and was studied by analysis of caspase activity and nuclear morphology. Involvement of lysosomal cathepsins was investigated using the cysteine cathepsin inhibitor z-FA-FMK and the cathepsin D inhibitor pepstatin A. The amounts of cellular and soluble Fas death receptor were determined by ELISA.

    Results. Release of cathepsins from the lysosomes to the cytosol was observed early in apoptosis. Cysteine cathepsins were found to be involved in activation of caspases in response to treatment with naphthazarin or anti-Fas antibodies, but inhibition of cysteine cathepsin activity was not sufficient to prevent cell death. Moreover, inhibition of cysteine cathepsin activity resulted in increased expression of the Fas death receptor, suggesting involvement of extracellular cysteine cathepsins in death receptor shedding.

    Emneord
    Caspases; cathepsin D; cell death; cysteine cathepsins; Fas death receptor; lysosomes; shedding; soluble Fas
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13203 (URN)10.1080/00016480510043422 (DOI)
    Tilgjengelig fra: 2008-04-17 Laget: 2008-04-17 Sist oppdatert: 2009-05-20
  • 38.
    Johansson, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Jerhammar, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Bradic Lindh, Maja
    Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Grenman, Reidar
    Turku University Hospital, Finland University of Turku, Finland .
    Munck-Wikland, Eva
    Karolinska University Hospital, Sweden .
    Ostman, Arne
    Karolinska Institute, Sweden .
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells2012Inngår i: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 10, nr 9, s. 1158-1168Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy.

  • 39.
    Johansson, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Cathrine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Regulation of apoptosis-associated lysosomal membrane permeabilization2010Inngår i: APOPTOSIS, ISSN 1360-8185, Vol. 15, nr 5, s. 527-540Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lysosomal membrane permeabilization (LMP) occurs in response to a large variety of cell death stimuli causing release of cathepsins from the lysosomal lumen into the cytosol where they participate in apoptosis signaling. In some settings, apoptosis induction is dependent on an early release of cathepsins, while under other circumstances LMP occurs late in the cell death process and contributes to amplification of the death signal. The mechanism underlying LMP is still incompletely understood; however, a growing body of evidence suggests that LMP may be governed by several distinct mechanisms that are likely engaged in a death stimulus- and cell-type-dependent fashion. In this review, factors contributing to permeabilization of the lysosomal membrane including reactive oxygen species, lysosomal membrane lipid composition, proteases, p53, and Bcl-2 family proteins, are described. Potential mechanisms to safeguard lysosomal integrity and confer resistance to lysosome-dependent cell death are also discussed.

  • 40.
    Johansson, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Mild, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Uno
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Cathrine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Antonsson, Bruno
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Cathepsin D-mediated processing of Bid at Phe24, Trp48, and Phe1832008Inngår i: International Journal of Experimental PathologyArtikkel i tidsskrift (Fagfellevurdert)
  • 41.
    Johansson, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Norberg-Spaak, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Role of lysosomal cathepsins in naphthazarin- and Fas-induced apoptosis in oral squamous cell carcinoma cells2006Inngår i: Acta Oto-Laryngologica, ISSN 0001-6489, Vol. 126, nr 1, s. 70-81Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Conclusion. Intracellular cysteine cathepsins are pro-apoptotic factors involved in activation of caspases in two oral squamous cell carcinoma (SCC) cell lines.

    Objective. To study the possible involvement of lysosomal cathepsins in oral SCC cell apoptosis.

    Material and methods. Apoptosis was induced in the two human oral SCC cell lines UT-SCC-20A and UT-SCC-24A using naphthazarin or anti-Fas antibodies, and was studied by analysis of caspase activity and nuclear morphology. Involvement of lysosomal cathepsins was investigated using the cysteine cathepsin inhibitor z-FA-FMK and the cathepsin D inhibitor pepstatin A. The amounts of cellular and soluble Fas death receptor were determined by ELISA.

    Results. Release of cathepsins from the lysosomes to the cytosol was observed early in apoptosis. Cysteine cathepsins were found to be involved in activation of caspases in response to treatment with naphthazarin or anti-Fas antibodies, but inhibition of cysteine cathepsin activity was not sufficient to prevent cell death. Moreover, inhibition of cysteine cathepsin activity resulted in increased expression of the Fas death receptor, suggesting involvement of extracellular cysteine cathepsins in death receptor shedding.

  • 42.
    Johansson, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Steen, Håkan
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine2003Inngår i: Cell Death and Differentiation, ISSN 1350-9047, Vol. 10, nr 11, s. 1253-1259Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is increasing evidence that proteases other than caspases, for example, the lysosomal cathepsins B, D and L, are involved in apoptotic cell death. In the present study, we present data that suggest a role for cathepsin D in staurosporine-induced apoptosis in human foreskin fibroblasts. Cathepsin D and cytochrome c were detected partially released to the cytosol after exposure to 0.1 µM staurosporine for 1 h. After 4 h, activation of caspase-9 and -3 was initiated and later caspase-8 activation and a decrease in full-length Bid were detected. Pretreatment of cells with the cathepsin D inhibitor, pepstatin A, prevented cytochrome c release and caspase activation, and delayed cell death. These results imply that cytosolic cathepsin D is a key mediator in staurosporine-induced apoptosis. Analysis of the relative sequence of apoptotic events indicates that, in this cell type, cathepsin D acts upstream of cytochrome c release and caspase activation.

  • 43. Jostarndt, K
    et al.
    Gellert, N
    Rubic, T
    Weber, C
    Kuhn, H
    Johansen, B
    Hrboticky, N
    Neuzil, Jiri
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Dissociation of apoptosis induction and CD36 upregulation by enzymatically modified low-density lipoprotein in monocytic cells2002Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 290, nr 3, s. 988-993Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Modified low-density lipoprotein (LDL) has been implicated as an initiating or amplifying factor in atherogenesis. Some of its biological activities, such as apoptosis induction and upregulation of the scavenger receptor CD36, appear to share common signaling pathways in cells of the cardiovascular system. Exposure of low-differentiated monocytic cells to LDL modified with 15-lipoxygenase and secretory phospholipase A(2) induced apoptosis and upregulated CD36. Cell treatment with constituents of modified LDL, such as 13-hydroxyoctadecadienoic acid (13-HODE), 25-hydroxycholesterol, and lysophosphatidyl choline, and with an unrelated apoptogen (TNF-related apoptosis-inducing ligand) induced apoptosis. In contrast, only 13-HODE caused upregulation of CD36 expression. Cotreatment with the pan-caspase inhibitor z.VAD-fmk resulted in suppression of apoptosis, but was without any effect on CD36 expression. These data indicate that in monocytic cells enzymatically modified LDL is capable of inducing both apoptosis and upregulation of CD36 expression. However, in our cellular model, the two induction processes appear to be causally unrelated. (C) 2002 Elsevier Science (USA).

  • 44.
    Kim, Woojin Scott
    et al.
    Prince of Wales Medical Research Institute, Randwick NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney NSW, Australia.
    Bhatia, Surabhi
    Prince of Wales Medical Research Institute, Randwick NSW, Australia.
    Elliott, David A
    Prince of Wales Medical Research Institute, Randwick NSW, Australia.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Geriatriska enheten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    McCann, Heather
    Prince of Wales Medical Research Institute, Randwick NSW, Australia.
    Halliday, Glenda M
    Prince of Wales Medical Research Institute, Randwick NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney NSW, Australia.
    Barnham, Kevin J
    Department of Pathology, University of Melbourne, VIC, Australia.
    Garner, Brett
    Prince of Wales Medical Research Institute, Randwick NSW, Australia; School of Biological Sciences, Faculty of Science, University of Wollongong, Wollongong NSW, Australia.
    Increased ATP-binding cassette transporter A1 expression in Alzheimer's disease hippocampal neurons2010Inngår i: Journal of Alzheimer's disease : JAD, ISSN 1875-8908, Vol. 21, nr 1, s. 193-205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ATP-binding cassette transporter A1 (ABCA1) reduces amyloid-beta burden in transgenic mouse models of Alzheimer's disease (AD). Associations between ABCA1 polymorphisms and AD risk are also established. Little is known regarding the regulation of ABCA1 expression in the brain and how this may be affected by AD. In the present study we assessed ABCA1 mRNA and protein expression in the hippocampus of AD cases compared to controls. ABCA1 was clearly expressed in hippocampal neurons and expression was increased two- to three-fold in AD cases. The increased hippocampal ABCA1 expression was associated with increased APOE and PUMA gene expression, implying an association with neuronal stress. Consistent with this, treatment of SK-N-SH neurons with amyloid-beta peptide resulted in a 48% loss in survival and a significant upregulation of ABCA1, APOE, and PUMA gene expression. Studies in young (2 month) and old (12 month) transgenic mice expressing a familial AD form of human amyloid-beta protein precursor and presenilin-1 revealed a significant age-dependent upregulation of hippocampal Abca1 compared to wild-type control mice. However, hippocampal Apoe and Puma gene expression were not correlated with increased Abca1 expression in mice. Our data indicate that ABCA1 is upregulated in AD hippocampal neurons potentially via an amyloid-beta-mediated pathway.

  • 45.
    Kishwar, Sultana
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Siddique, M.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Israr, Muhammad Qadir
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Nour, Omer
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Willander, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska högskolan.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Investigation of the phototoxic effect of ZnO nanorods on fibroblasts and melanoma human cells2014Inngår i: Laser Physics Letters, ISSN 1612-2011, E-ISSN 1612-202X, Vol. 11, nr 11, artikkel-id 115606Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Photo-cytotoxicity of zinc oxide (ZnO) nanowires (NWs) either bare or conjugated with photosensitizers was studied in dark and after ultraviolet light exposure, in human melanoma and foreskin fibroblast cells. ZnO NWs were grown on the capillary tip and then coated with photosensitizer. This coated tip was used as pointer for intracellular insertion of ZnO NWs and photosensitizer. ZnO NWs pointer was inserted into a specific cell and then irradiated with ultraviolet (UVA), which led to loss of mitochondrial membrane potential, as estimated by loss of the Mitotracker Red staining. Dissolved ZnO NWs showed cytotoxicity as detected by MTT viability assay and morphological evaluation. UVA-irradiation enhanced the toxicity and caused the production of reactive oxygen species (ROS) resulting in cell necrosis. ZnO NWs were photo-toxic for both normal and cancer cells, questioning their bio-safety.

  • 46.
    Klionsky, Daniel J
    et al.
    Life Sciences Institute; Department of Molecular, Cellular and Developmental Biology; Department of Biological Chemistry; University of Michigan; Ann Arbor, MI, USA .
    Abdalla, Fabio C
    Laboratory of Structural and Functional Biology; Federal University of São Carlos (UFSCar); Campus Sorocaba; São Paulo State, Brazil .
    Abeliovich, Hagai
    Department of Biochemistry and Food Science; Hebrew University; Rehovot, Israel .
    Abraham, Robert T
    Acevedo-Arozena, Abraham
    Adeli, Khosrow
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Agnello, Maria
    Agostinis, Patrizia
    Aguirre-Ghiso, Julio A
    Ahn, Hyung Jun
    Ait-Mohamed, Ouardia
    Ait-Si-Ali, Slimane
    Akematsu, Takahiko
    Akira, Shizuo
    Al-Younes, Hesham M
    Al-Zeer, Munir A
    Albert, Matthew L
    Albin, Roger L
    Alegre-Abarrategui, Javier
    Aleo, Maria Francesca
    Alirezaei, Mehrdad
    Almasan, Alexandru
    Almonte-Becerril, Maylin
    Amano, Atsuo
    Amaravadi, Ravi
    Amarnath, Shoba
    Amer, Amal O
    Andrieu-Abadie, Nathalie
    Anantharam, Vellareddy
    Ann, David K
    Anoopkumar-Dukie, Shailendra
    Aoki, Hiroshi
    Apostolova, Nadezda
    Auberger, Patrick
    Baba, Misuzu
    Backues, Steven K
    Baehrecke, Eric H
    Bahr, Ben A
    Bai, Xue-Yuan
    Bailly, Yannick
    Baiocchi, Robert
    Baldini, Giulia
    Balduini, Walter
    Ballabio, Andrea
    Bamber, Bruce A
    Bampton, Edward T W
    Bánhegyi, Gábor
    Bartholomew, Clinton R
    Bassham, Diane C
    Bast, Robert C
    Batoko, Henri
    Bay, Boon-Huat
    Beau, Isabelle
    Béchet, Daniel M
    Begley, Thomas J
    Behl, Christian
    Behrends, Christian
    Bekri, Soumeya
    Bellaire, Bryan
    Bendall, Linda J
    Benetti, Luca
    Berliocchi, Laura
    Bernardi, Henri
    Bernassola, Francesca
    Besteiro, Sébastien
    Bhatia-Kissova, Ingrid
    Bi, Xiaoning
    Biard-Piechaczyk, Martine
    Blum, Janice S
    Boise, Lawrence H
    Bonaldo, Paolo
    Boone, David L
    Bornhauser, Beat C
    Bortoluci, Karina R
    Bossis, Ioannis
    Bost, Frédéric
    Bourquin, Jean-Pierre
    Boya, Patricia
    Boyer-Guittaut, Michaël
    Bozhkov, Peter V
    Brady, Nathan R
    Brancolini, Claudio
    Brech, Andreas
    Brenman, Jay E
    Brennand, Ana
    Bresnick, Emery H
    Brest, Patrick
    Bridges, Dave
    Bristol, Molly L
    Brookes, Paul S
    Brown, Eric J
    Brumell, John H
    Brunetti-Pierri, Nicola
    Brunk, Ulf T
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bulman, Dennis E
    Bultman, Scott J
    Bultynck, Geert
    Burbulla, Lena F
    Bursch, Wilfried
    Butchar, Jonathan P
    Buzgariu, Wanda
    Bydlowski, Sergio P
    Cadwell, Ken
    Cahová, Monika
    Cai, Dongsheng
    Cai, Jiyang
    Cai, Qian
    Calabretta, Bruno
    Calvo-Garrido, Javier
    Camougrand, Nadine
    Campanella, Michelangelo
    Campos-Salinas, Jenny
    Candi, Eleonora
    Cao, Lizhi
    Caplan, Allan B
    Carding, Simon R
    Cardoso, Sandra M
    Carew, Jennifer S
    Carlin, Cathleen R
    Carmignac, Virginie
    Carneiro, Leticia A M
    Carra, Serena
    Caruso, Rosario A
    Casari, Giorgio
    Casas, Caty
    Castino, Roberta
    Cebollero, Eduardo
    Cecconi, Francesco
    Celli, Jean
    Chaachouay, Hassan
    Chae, Han-Jung
    Chai, Chee-Yin
    Chan, David C
    Chan, Edmond Y
    Chang, Raymond Chuen-Chung
    Che, Chi-Ming
    Chen, Ching-Chow
    Chen, Guang-Chao
    Chen, Guo-Qiang
    Chen, Min
    Chen, Quan
    Chen, Steve S-L
    Chen, WenLi
    Chen, Xi
    Chen, Xiangmei
    Chen, Xiequn
    Chen, Ye-Guang
    Chen, Yingyu
    Chen, Yongqiang
    Chen, Yu-Jen
    Chen, Zhixiang
    Cheng, Alan
    Cheng, Christopher H K
    Cheng, Yan
    Cheong, Heesun
    Cheong, Jae-Ho
    Cherry, Sara
    Chess-Williams, Russ
    Cheung, Zelda H
    Chevet, Eric
    Chiang, Hui-Ling
    Chiarelli, Roberto
    Chiba, Tomoki
    Chin, Lih-Shen
    Chiou, Shih-Hwa
    Chisari, Francis V
    Cho, Chi Hin
    Cho, Dong-Hyung
    Choi, Augustine M K
    Choi, DooSeok
    Choi, Kyeong Sook
    Choi, Mary E
    Chouaib, Salem
    Choubey, Divaker
    Choubey, Vinay
    Chu, Charleen T
    Chuang, Tsung-Hsien
    Chueh, Sheau-Huei
    Chun, Taehoon
    Chwae, Yong-Joon
    Chye, Mee-Len
    Ciarcia, Roberto
    Ciriolo, Maria R
    Clague, Michael J
    Clark, Robert S B
    Clarke, Peter G H
    Clarke, Robert
    Codogno, Patrice
    Coller, Hilary A
    Colombo, María I
    Comincini, Sergio
    Condello, Maria
    Condorelli, Fabrizio
    Cookson, Mark R
    Coombs, Graham H
    Coppens, Isabelle
    Corbalan, Ramon
    Cossart, Pascale
    Costelli, Paola
    Costes, Safia
    Coto-Montes, Ana
    Couve, Eduardo
    Coxon, Fraser P
    Cregg, James M
    Crespo, José L
    Cronjé, Marianne J
    Cuervo, Ana Maria
    Cullen, Joseph J
    Czaja, Mark J
    D'Amelio, Marcello
    Darfeuille-Michaud, Arlette
    Davids, Lester M
    Davies, Faith E
    De Felici, Massimo
    de Groot, John F
    de Haan, Cornelis A M
    De Martino, Luisa
    De Milito, Angelo
    De Tata, Vincenzo
    Debnath, Jayanta
    Degterev, Alexei
    Dehay, Benjamin
    Delbridge, Lea M D
    Demarchi, Francesca
    Deng, Yi Zhen
    Dengjel, Jörn
    Dent, Paul
    Denton, Donna
    Deretic, Vojo
    Desai, Shyamal D
    Devenish, Rodney J
    Di Gioacchino, Mario
    Di Paolo, Gilbert
    Di Pietro, Chiara
    Díaz-Araya, Guillermo
    Díaz-Laviada, Inés
    Diaz-Meco, Maria T
    Diaz-Nido, Javier
    Dikic, Ivan
    Dinesh-Kumar, Savithramma P
    Ding, Wen-Xing
    Distelhorst, Clark W
    Diwan, Abhinav
    Djavaheri-Mergny, Mojgan
    Dokudovskaya, Svetlana
    Dong, Zheng
    Dorsey, Frank C
    Dosenko, Victor
    Dowling, James J
    Doxsey, Stephen
    Dreux, Marlène
    Drew, Mark E
    Duan, Qiuhong
    Duchosal, Michel A
    Duff, Karen
    Dugail, Isabelle
    Durbeej, Madeleine
    Duszenko, Michael
    Edelstein, Charles L
    Edinger, Aimee L
    Egea, Gustavo
    Eichinger, Ludwig
    Eissa, N Tony
    Ekmekcioglu, Suhendan
    El-Deiry, Wafik S
    Elazar, Zvulun
    Elgendy, Mohamed
    Ellerby, Lisa M
    Eng, Kai Er
    Engelbrecht, Anna-Mart
    Engelender, Simone
    Erenpreisa, Jekaterina
    Escalante, Ricardo
    Esclatine, Audrey
    Eskelinen, Eeva-Liisa
    Espert, Lucile
    Espina, Virginia
    Fan, Huizhou
    Fan, Jia
    Fan, Qi-Wen
    Fan, Zhen
    Fang, Shengyun
    Fang, Yongqi
    Fanto, Manolis
    Fanzani, Alessandro
    Farkas, Thomas
    Farré, Jean-Claude
    Faure, Mathias
    Fechheimer, Marcus
    Feng, Carl G
    Feng, Jian
    Feng, Qili
    Feng, Youji
    Fésüs, László
    Feuer, Ralph
    Figueiredo-Pereira, Maria E
    Fimia, Gian Maria
    Fingar, Diane C
    Finkbeiner, Steven
    Finkel, Toren
    Finley, Kim D
    Fiorito, Filomena
    Fisher, Edward A
    Fisher, Paul B
    Flajolet, Marc
    Florez-McClure, Maria L
    Florio, Salvatore
    Fon, Edward A
    Fornai, Francesco
    Fortunato, Franco
    Fotedar, Rati
    Fowler, Daniel H
    Fox, Howard S
    Franco, Rodrigo
    Frankel, Lisa B
    Fransen, Marc
    Fuentes, José M
    Fueyo, Juan
    Fujii, Jun
    Fujisaki, Kozo
    Fujita, Eriko
    Fukuda, Mitsunori
    Furukawa, Ruth H
    Gaestel, Matthias
    Gailly, Philippe
    Gajewska, Malgorzata
    Galliot, Brigitte
    Galy, Vincent
    Ganesh, Subramaniam
    Ganetzky, Barry
    Ganley, Ian G
    Gao, Fen-Biao
    Gao, George F
    Gao, Jinming
    Garcia, Lorena
    Garcia-Manero, Guillermo
    Garcia-Marcos, Mikel
    Garmyn, Marjan
    Gartel, Andrei L
    Gatti, Evelina
    Gautel, Mathias
    Gawriluk, Thomas R
    Gegg, Matthew E
    Geng, Jiefei
    Germain, Marc
    Gestwicki, Jason E
    Gewirtz, David A
    Ghavami, Saeid
    Ghosh, Pradipta
    Giammarioli, Anna M
    Giatromanolaki, Alexandra N
    Gibson, Spencer B
    Gilkerson, Robert W
    Ginger, Michael L
    Goncu, Ebru
    Gongora, Céline
    Gonzalez, Claudio D
    Gonzalez, Ramon
    González-Estévez, Cristina
    González-Polo, Rosa Ana
    Gonzalez-Rey, Elena
    Gorbunov, Nikolai V
    Gorski, Sharon
    Goruppi, Sandro
    Gottlieb, Roberta A
    Gozuacik, Devrim
    Granato, Giovanna Elvira
    Grant, Gary D
    Green, Kim N
    Gregorc, Aleš
    Gros, Frédéric
    Grose, Charles
    Grunt, Thomas W
    Gual, Philippe
    Guan, Jun-Lin
    Guan, Kun-Liang
    Guichard, Sylvie M
    Gukovskaya, Anna S
    Gukovsky, Ilya
    Gunst, Jan
    Gustafsson, Asa B
    Halayko, Andrew J
    Hale, Amber N
    Halonen, Sandra K
    Hamasaki, Maho
    Han, Feng
    Han, Ting
    Hancock, Michael K
    Hansen, Malene
    Harada, Hisashi
    Harada, Masaru
    Hardt, Stefan E
    Harper, J Wade
    Harris, Adrian L
    Harris, James
    Harris, Steven D
    Hébert, Marie-Joseé
    Heidenreich, Kim A
    Helfrich, Miep H
    Helgason, Gudmundur V
    Henske, Elizabeth P
    Herman, Brian
    Herman, Paul K
    Hetz, Claudio
    Hilfiker, Sabine
    Hill, Joseph A
    Hocking, Lynne J
    Hofman, Paul
    Hofmann, Thomas G
    Höhfeld, Jörg
    Holyoake, Tessa L
    Hong, Ming-Huang
    Hood, David A
    Hotamisligil, Gökhan S
    Houwerzijl, Ewout J
    Høyer-Hansen, Maria
    Hu, Bingren
    Hu, Chien-An A
    Hu, Hong-Ming
    Hua, Ya
    Huang, Canhua
    Huang, Ju
    Huang, Shengbing
    Huang, Wei-Pang
    Huber, Tobias B
    Huh, Won-Ki
    Hung, Tai-Ho
    Hupp, Ted R
    Hur, Gang Min
    Hurley, James B
    Hussain, Sabah N A
    Hussey, Patrick J
    Hwang, Jung Jin
    Hwang, Seungmin
    Ichihara, Atsuhiro
    Ilkhanizadeh, Shirin
    Inoki, Ken
    Into, Takeshi
    Iovane, Valentina
    Iovanna, Juan L
    Ip, Nancy Y
    Isaka, Yoshitaka
    Ishida, Hiroyuki
    Isidoro, Ciro
    Isobe, Ken-ichi
    Iwasaki, Akiko
    Izquierdo, Marta
    Izumi, Yotaro
    Jaakkola, Panu M
    Jäättelä, Marja
    Jackson, George R
    Jackson, William T
    Janji, Bassam
    Jendrach, Marina
    Jeon, Ju-Hong
    Jeung, Eui-Bae
    Jiang, Hong
    Jiang, Hongchi
    Jiang, Jean X
    Jiang, Ming
    Jiang, Qing
    Jiang, Xuejun
    Jiang, Xuejun
    Jiménez, Alberto
    Jin, Meiyan
    Jin, Shengkan
    Joe, Cheol O
    Johansen, Terje
    Johnson, Daniel E
    Johnson, Gail V W
    Jones, Nicola L
    Joseph, Bertrand
    Joseph, Suresh K
    Joubert, Annie M
    Juhász, Gábor
    Juillerat-Jeanneret, Lucienne
    Jung, Chang Hwa
    Jung, Yong-Keun
    Kaarniranta, Kai
    Kaasik, Allen
    Kabuta, Tomohiro
    Kadowaki, Motoni
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Kamada, Yoshiaki
    Kaminskyy, Vitaliy O
    Kampinga, Harm H
    Kanamori, Hiromitsu
    Kang, Chanhee
    Kang, Khong Bee
    Kang, Kwang Il
    Kang, Rui
    Kang, Yoon-A
    Kanki, Tomotake
    Kanneganti, Thirumala-Devi
    Kanno, Haruo
    Kanthasamy, Anumantha G
    Kanthasamy, Arthi
    Karantza, Vassiliki
    Kaushal, Gur P
    Kaushik, Susmita
    Kawazoe, Yoshinori
    Ke, Po-Yuan
    Kehrl, John H
    Kelekar, Ameeta
    Kerkhoff, Claus
    Kessel, David H
    Khalil, Hany
    Kiel, Jan A K W
    Kiger, Amy A
    Kihara, Akio
    Kim, Deok Ryong
    Kim, Do-Hyung
    Kim, Dong-Hou
    Kim, Eun-Kyoung
    Kim, Hyung-Ryong
    Kim, Jae-Sung
    Kim, Jeong Hun
    Kim, Jin Cheon
    Kim, John K
    Kim, Peter K
    Kim, Seong Who
    Kim, Yong-Sun
    Kim, Yonghyun
    Kimchi, Adi
    Kimmelman, Alec C
    King, Jason S
    Kinsella, Timothy J
    Kirkin, Vladimir
    Kirshenbaum, Lorrie A
    Kitamoto, Katsuhiko
    Kitazato, Kaio
    Klein, Ludger
    Klimecki, Walter T
    Klucken, Jochen
    Knecht, Erwin
    Ko, Ben C B
    Koch, Jan C
    Koga, Hiroshi
    Koh, Jae-Young
    Koh, Young Ho
    Koike, Masato
    Komatsu, Masaaki
    Kominami, Eiki
    Kong, Hee Jeong
    Kong, Wei-Jia
    Korolchuk, Viktor I
    Kotake, Yaichiro
    Koukourakis, Michael I
    Kouri Flores, Juan B
    Kovács, Attila L
    Kraft, Claudine
    Krainc, Dimitri
    Krämer, Helmut
    Kretz-Remy, Carole
    Krichevsky, Anna M
    Kroemer, Guido
    Krüger, Rejko
    Krut, Oleg
    Ktistakis, Nicholas T
    Kuan, Chia-Yi
    Kucharczyk, Roza
    Kumar, Ashok
    Kumar, Raj
    Kumar, Sharad
    Kundu, Mondira
    Kung, Hsing-Jien
    Kurz, Tino
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kwon, Ho Jeong
    La Spada, Albert R
    Lafont, Frank
    Lamark, Trond
    Landry, Jacques
    Lane, Jon D
    Lapaquette, Pierre
    Laporte, Jocelyn F
    László, Lajos
    Lavandero, Sergio
    Lavoie, Josée N
    Layfield, Robert
    Lazo, Pedro A
    Le, Weidong
    Le Cam, Laurent
    Ledbetter, Daniel J
    Lee, Alvin J X
    Lee, Byung-Wan
    Lee, Gyun Min
    Lee, Jongdae
    Lee, Ju-Hyun
    Lee, Michael
    Lee, Myung-Shik
    Lee, Sug Hyung
    Leeuwenburgh, Christiaan
    Legembre, Patrick
    Legouis, Renaud
    Lehmann, Michael
    Lei, Huan-Yao
    Lei, Qun-Ying
    Leib, David A
    Leiro, José
    Lemasters, John J
    Lemoine, Antoinette
    Lesniak, Maciej S
    Lev, Dina
    Levenson, Victor V
    Levine, Beth
    Levy, Efrat
    Li, Faqiang
    Li, Jun-Lin
    Li, Lian
    Li, Sheng
    Li, Weijie
    Li, Xue-Jun
    Li, Yan-bo
    Li, Yi-Ping
    Liang, Chengyu
    Liang, Qiangrong
    Liao, Yung-Feng
    Liberski, Pawel P
    Lieberman, Andrew
    Lim, Hyunjung J
    Lim, Kah-Leong
    Lim, Kyu
    Lin, Chiou-Feng
    Lin, Fu-Cheng
    Lin, Jian
    Lin, Jiandie D
    Lin, Kui
    Lin, Wan-Wan
    Lin, Weei-Chin
    Lin, Yi-Ling
    Linden, Rafael
    Lingor, Paul
    Lippincott-Schwartz, Jennifer
    Lisanti, Michael P
    Liton, Paloma B
    Liu, Bo
    Liu, Chun-Feng
    Liu, Kaiyu
    Liu, Leyuan
    Liu, Qiong A
    Liu, Wei
    Liu, Young-Chau
    Liu, Yule
    Lockshin, Richard A
    Lok, Chun-Nam
    Lonial, Sagar
    Loos, Benjamin
    Lopez-Berestein, Gabriel
    López-Otín, Carlos
    Lossi, Laura
    Lotze, Michael T
    Lőw, Peter
    Lu, Binfeng
    Lu, Bingwei
    Lu, Bo
    Lu, Zhen
    Luciano, Frédéric
    Lukacs, Nicholas W
    Lund, Anders H
    Lynch-Day, Melinda A
    Ma, Yong
    Macian, Fernando
    MacKeigan, Jeff P
    Macleod, Kay F
    Madeo, Frank
    Maiuri, Luigi
    Maiuri, Maria Chiara
    Malagoli, Davide
    Malicdan, May Christine V
    Malorni, Walter
    Man, Na
    Mandelkow, Eva-Maria
    Manon, Stéphen
    Manov, Irena
    Mao, Kai
    Mao, Xiang
    Mao, Zixu
    Marambaud, Philippe
    Marazziti, Daniela
    Marcel, Yves L
    Marchbank, Katie
    Marchetti, Piero
    Marciniak, Stefan J
    Marcondes, Mateus
    Mardi, Mohsen
    Marfe, Gabriella
    Mariño, Guillermo
    Markaki, Maria
    Marten, Mark R
    Martin, Seamus J
    Martinand-Mari, Camille
    Martinet, Wim
    Martinez-Vicente, Marta
    Masini, Matilde
    Matarrese, Paola
    Matsuo, Saburo
    Matteoni, Raffaele
    Mayer, Andreas
    Mazure, Nathalie M
    McConkey, David J
    McConnell, Melanie J
    McDermott, Catherine
    McDonald, Christine
    McInerney, Gerald M
    McKenna, Sharon L
    McLaughlin, BethAnn
    McLean, Pamela J
    McMaster, Christopher R
    McQuibban, G Angus
    Meijer, Alfred J
    Meisler, Miriam H
    Meléndez, Alicia
    Melia, Thomas J
    Melino, Gerry
    Mena, Maria A
    Menendez, Javier A
    Menna-Barreto, Rubem F S
    Menon, Manoj B
    Menzies, Fiona M
    Mercer, Carol A
    Merighi, Adalberto
    Merry, Diane E
    Meschini, Stefania
    Meyer, Christian G
    Meyer, Thomas F
    Miao, Chao-Yu
    Miao, Jun-Ying
    Michels, Paul A M
    Michiels, Carine
    Mijaljica, Dalibor
    Milojkovic, Ana
    Minucci, Saverio
    Miracco, Clelia
    Miranti, Cindy K
    Mitroulis, Ioannis
    Miyazawa, Keisuke
    Mizushima, Noboru
    Mograbi, Baharia
    Mohseni, Simin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Molero, Xavier
    Mollereau, Bertrand
    Mollinedo, Faustino
    Momoi, Takashi
    Monastyrska, Iryna
    Monick, Martha M
    Monteiro, Mervyn J
    Moore, Michael N
    Mora, Rodrigo
    Moreau, Kevin
    Moreira, Paula I
    Moriyasu, Yuji
    Moscat, Jorge
    Mostowy, Serge
    Mottram, Jeremy C
    Motyl, Tomasz
    Moussa, Charbel E-H
    Müller, Sylke
    Muller, Sylviane
    Münger, Karl
    Münz, Christian
    Murphy, Leon O
    Murphy, Maureen E
    Musarò, Antonio
    Mysorekar, Indira
    Nagata, Eiichiro
    Nagata, Kazuhiro
    Nahimana, Aimable
    Nair, Usha
    Nakagawa, Toshiyuki
    Nakahira, Kiichi
    Nakano, Hiroyasu
    Nakatogawa, Hitoshi
    Nanjundan, Meera
    Naqvi, Naweed I
    Narendra, Derek P
    Narita, Masashi
    Navarro, Miguel
    Nawrocki, Steffan T
    Nazarko, Taras Y
    Nemchenko, Andriy
    Netea, Mihai G
    Neufeld, Thomas P
    Ney, Paul A
    Nezis, Ioannis P
    Nguyen, Huu Phuc
    Nie, Daotai
    Nishino, Ichizo
    Nislow, Corey
    Nixon, Ralph A
    Noda, Takeshi
    Noegel, Angelika A
    Nogalska, Anna
    Noguchi, Satoru
    Notterpek, Lucia
    Novak, Ivana
    Nozaki, Tomoyoshi
    Nukina, Nobuyuki
    Nürnberger, Thorsten
    Nyfeler, Beat
    Obara, Keisuke
    Oberley, Terry D
    Oddo, Salvatore
    Ogawa, Michinaga
    Ohashi, Toya
    Okamoto, Koji
    Oleinick, Nancy L
    Oliver, F Javier
    Olsen, Laura J
    Olsson, Stefan
    Opota, Onya
    Osborne, Timothy F
    Ostrander, Gary K
    Otsu, Kinya
    Ou, Jing-hsiung James
    Ouimet, Mireille
    Overholtzer, Michael
    Ozpolat, Bulent
    Paganetti, Paolo
    Pagnini, Ugo
    Pallet, Nicolas
    Palmer, Glen E
    Palumbo, Camilla
    Pan, Tianhong
    Panaretakis, Theocharis
    Pandey, Udai Bhan
    Papackova, Zuzana
    Papassideri, Issidora
    Paris, Irmgard
    Park, Junsoo
    Park, Ohkmae K
    Parys, Jan B
    Parzych, Katherine R
    Patschan, Susann
    Patterson, Cam
    Pattingre, Sophie
    Pawelek, John M
    Peng, Jianxin
    Perlmutter, David H
    Perrotta, Ida
    Perry, George
    Pervaiz, Shazib
    Peter, Matthias
    Peters, Godefridus J
    Petersen, Morten
    Petrovski, Goran
    Phang, James M
    Piacentini, Mauro
    Pierre, Philippe
    Pierrefite-Carle, Valérie
    Pierron, Gérard
    Pinkas-Kramarski, Ronit
    Piras, Antonio
    Piri, Natik
    Platanias, Leonidas C
    Pöggeler, Stefanie
    Poirot, Marc
    Poletti, Angelo
    Poüs, Christian
    Pozuelo-Rubio, Mercedes
    Prætorius-Ibba, Mette
    Prasad, Anil
    Prescott, Mark
    Priault, Muriel
    Produit-Zengaffinen, Nathalie
    Progulske-Fox, Ann
    Proikas-Cezanne, Tassula
    Przedborski, Serge
    Przyklenk, Karin
    Puertollano, Rosa
    Puyal, Julien
    Qian, Shu-Bing
    Qin, Liang
    Qin, Zheng-Hong
    Quaggin, Susan E
    Raben, Nina
    Rabinowich, Hannah
    Rabkin, Simon W
    Rahman, Irfan
    Rami, Abdelhaq
    Ramm, Georg
    Randall, Glenn
    Randow, Felix
    Rao, V Ashutosh
    Rathmell, Jeffrey C
    Ravikumar, Brinda
    Ray, Swapan K
    Reed, Bruce H
    Reed, John C
    Reggiori, Fulvio
    Régnier-Vigouroux, Anne
    Reichert, Andreas S
    Reiners, John J
    Reiter, Russel J
    Ren, Jun
    Revuelta, José L
    Rhodes, Christopher J
    Ritis, Konstantinos
    Rizzo, Elizete
    Robbins, Jeffrey
    Roberge, Michel
    Roca, Hernan
    Roccheri, Maria C
    Rocchi, Stephane
    Rodemann, H Peter
    Rodríguez de Córdoba, Santiago
    Rohrer, Bärbel
    Roninson, Igor B
    Rosen, Kirill
    Rost-Roszkowska, Magdalena M
    Rouis, Mustapha
    Rouschop, Kasper M A
    Rovetta, Francesca
    Rubin, Brian P
    Rubinsztein, David C
    Ruckdeschel, Klaus
    Rucker, Edmund B
    Rudich, Assaf
    Rudolf, Emil
    Ruiz-Opazo, Nelson
    Russo, Rossella
    Rusten, Tor Erik
    Ryan, Kevin M
    Ryter, Stefan W
    Sabatini, David M
    Sadoshima, Junichi
    Saha, Tapas
    Saitoh, Tatsuya
    Sakagami, Hiroshi
    Sakai, Yasuyoshi
    Salekdeh, Ghasem Hoseini
    Salomoni, Paolo
    Salvaterra, Paul M
    Salvesen, Guy
    Salvioli, Rosa
    Sanchez, Anthony M J
    Sánchez-Alcázar, José A
    Sánchez-Prieto, Ricardo
    Sandri, Marco
    Sankar, Uma
    Sansanwal, Poonam
    Santambrogio, Laura
    Saran, Shweta
    Sarkar, Sovan
    Sarwal, Minnie
    Sasakawa, Chihiro
    Sasnauskiene, Ausra
    Sass, Miklós
    Sato, Ken
    Sato, Miyuki
    Schapira, Anthony H V
    Scharl, Michael
    Schätzl, Hermann M
    Scheper, Wiep
    Schiaffino, Stefano
    Schneider, Claudio
    Schneider, Marion E
    Schneider-Stock, Regine
    Schoenlein, Patricia V
    Schorderet, Daniel F
    Schüller, Christoph
    Schwartz, Gary K
    Scorrano, Luca
    Sealy, Linda
    Seglen, Per O
    Segura-Aguilar, Juan
    Seiliez, Iban
    Seleverstov, Oleksandr
    Sell, Christian
    Seo, Jong Bok
    Separovic, Duska
    Setaluri, Vijayasaradhi
    Setoguchi, Takao
    Settembre, Carmine
    Shacka, John J
    Shanmugam, Mala
    Shapiro, Irving M
    Shaulian, Eitan
    Shaw, Reuben J
    Shelhamer, James H
    Shen, Han-Ming
    Shen, Wei-Chiang
    Sheng, Zu-Hang
    Shi, Yang
    Shibuya, Kenichi
    Shidoji, Yoshihiro
    Shieh, Jeng-Jer
    Shih, Chwen-Ming
    Shimada, Yohta
    Shimizu, Shigeomi
    Shintani, Takahiro
    Shirihai, Orian S
    Shore, Gordon C
    Sibirny, Andriy A
    Sidhu, Stan B
    Sikorska, Beata
    Silva-Zacarin, Elaine C M
    Simmons, Alison
    Simon, Anna Katharina
    Simon, Hans-Uwe
    Simone, Cristiano
    Simonsen, Anne
    Sinclair, David A
    Singh, Rajat
    Sinha, Debasish
    Sinicrope, Frank A
    Sirko, Agnieszka
    Siu, Parco M
    Sivridis, Efthimios
    Skop, Vojtech
    Skulachev, Vladimir P
    Slack, Ruth S
    Smaili, Soraya S
    Smith, Duncan R
    Soengas, Maria S
    Soldati, Thierry
    Song, Xueqin
    Sood, Anil K
    Soong, Tuck Wah
    Sotgia, Federica
    Spector, Stephen A
    Spies, Claudia D
    Springer, Wolfdieter
    Srinivasula, Srinivasa M
    Stefanis, Leonidas
    Steffan, Joan S
    Stendel, Ruediger
    Stenmark, Harald
    Stephanou, Anastasis
    Stern, Stephan T
    Sternberg, Cinthya
    Stork, Björn
    Strålfors, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Subauste, Carlos S
    Sui, Xinbing
    Sulzer, David
    Sun, Jiaren
    Sun, Shi-Yong
    Sun, Zhi-Jun
    Sung, Joseph J Y
    Suzuki, Kuninori
    Suzuki, Toshihiko
    Swanson, Michele S
    Swanton, Charles
    Sweeney, Sean T
    Sy, Lai-King
    Szabadkai, Gyorgy
    Tabas, Ira
    Taegtmeyer, Heinrich
    Tafani, Marco
    Takács-Vellai, Krisztina
    Takano, Yoshitaka
    Takegawa, Kaoru
    Takemura, Genzou
    Takeshita, Fumihiko
    Talbot, Nicholas J
    Tan, Kevin S W
    Tanaka, Keiji
    Tanaka, Kozo
    Tang, Daolin
    Tang, Dingzhong
    Tanida, Isei
    Tannous, Bakhos A
    Tavernarakis, Nektarios
    Taylor, Graham S
    Taylor, Gregory A
    Taylor, J Paul
    Terada, Lance S
    Terman, Alexei
    Tettamanti, Gianluca
    Thevissen, Karin
    Thompson, Craig B
    Thorburn, Andrew
    Thumm, Michael
    Tian, FengFeng
    Tian, Yuan
    Tocchini-Valentini, Glauco
    Tolkovsky, Aviva M
    Tomino, Yasuhiko
    Tönges, Lars
    Tooze, Sharon A
    Tournier, Cathy
    Tower, John
    Towns, Roberto
    Trajkovic, Vladimir
    Travassos, Leonardo H
    Tsai, Ting-Fen
    Tschan, Mario P
    Tsubata, Takeshi
    Tsung, Allan
    Turk, Boris
    Turner, Lorianne S
    Tyagi, Suresh C
    Uchiyama, Yasuo
    Ueno, Takashi
    Umekawa, Midori
    Umemiya-Shirafuji, Rika
    Unni, Vivek K
    Vaccaro, Maria I
    Valente, Enza Maria
    Van den Berghe, Greet
    van der Klei, Ida J
    van Doorn, Wouter
    van Dyk, Linda F
    van Egmond, Marjolein
    van Grunsven, Leo A
    Vandenabeele, Peter
    Vandenberghe, Wim P
    Vanhorebeek, Ilse
    Vaquero, Eva C
    Velasco, Guillermo
    Vellai, Tibor
    Vicencio, Jose Miguel
    Vierstra, Richard D
    Vila, Miquel
    Vindis, Cécile
    Viola, Giampietro
    Viscomi, Maria Teresa
    Voitsekhovskaja, Olga V
    von Haefen, Clarissa
    Votruba, Marcela
    Wada, Keiji
    Wade-Martins, Richard
    Walker, Cheryl L
    Walsh, Craig M
    Walter, Jochen
    Wan, Xiang-Bo
    Wang, Aimin
    Wang, Chenguang
    Wang, Dawei
    Wang, Fan
    Wang, Fen
    Wang, Guanghui
    Wang, Haichao
    Wang, Hong-Gang
    Wang, Horng-Dar
    Wang, Jin
    Wang, Ke
    Wang, Mei
    Wang, Richard C
    Wang, Xinglong
    Wang, Xuejun
    Wang, Ying-Jan
    Wang, Yipeng
    Wang, Zhen
    Wang, Zhigang Charles
    Wang, Zhinong
    Wansink, Derick G
    Ward, Diane M
    Watada, Hirotaka
    Waters, Sarah L
    Webster, Paul
    Wei, Lixin
    Weihl, Conrad C
    Weiss, William A
    Welford, Scott M
    Wen, Long-Ping
    Whitehouse, Caroline A
    Whitton, J Lindsay
    Whitworth, Alexander J
    Wileman, Tom
    Wiley, John W
    Wilkinson, Simon
    Willbold, Dieter
    Williams, Roger L
    Williamson, Peter R
    Wouters, Bradly G
    Wu, Chenghan
    Wu, Dao-Cheng
    Wu, William K K
    Wyttenbach, Andreas
    Xavier, Ramnik J
    Xi, Zhijun
    Xia, Pu
    Xiao, Gengfu
    Xie, Zhiping
    Xie, Zhonglin
    Xu, Da-zhi
    Xu, Jianzhen
    Xu, Liang
    Xu, Xiaolei
    Yamamoto, Ai
    Yamamoto, Akitsugu
    Yamashina, Shunhei
    Yamashita, Michiaki
    Yan, Xianghua
    Yanagida, Mitsuhiro
    Yang, Dun-Sheng
    Yang, Elizabeth
    Yang, Jin-Ming
    Yang, Shi Yu
    Yang, Wannian
    Yang, Wei Yuan
    Yang, Zhifen
    Yao, Meng-Chao
    Yao, Tso-Pang
    Yeganeh, Behzad
    Yen, Wei-Lien
    Yin, Jia-jing
    Yin, Xiao-Ming
    Yoo, Ook-Joon
    Yoon, Gyesoon
    Yoon, Seung-Yong
    Yorimitsu, Tomohiro
    Yoshikawa, Yuko
    Yoshimori, Tamotsu
    Yoshimoto, Kohki
    You, Ho Jin
    Youle, Richard J
    Younes, Anas
    Yu, Li
    Yu, Long
    Yu, Seong-Woon
    Yu, Wai Haung
    Yuan, Zhi-Min
    Yue, Zhenyu
    Yun, Cheol-Heui
    Yuzaki, Michisuke
    Zabirnyk, Olga
    Silva-Zacarin, Elaine
    Zacks, David
    Zacksenhaus, Eldad
    Zaffaroni, Nadia
    Zakeri, Zahra
    Zeh, Herbert J
    Zeitlin, Scott O
    Zhang, Hong
    Zhang, Hui-Ling
    Zhang, Jianhua
    Zhang, Jing-Pu
    Zhang, Lin
    Zhang, Long
    Zhang, Ming-Yong
    Zhang, Xu Dong
    Zhao, Mantong
    Zhao, Yi-Fang
    Zhao, Ying
    Zhao, Zhizhuang J
    Zheng, Xiaoxiang
    Zhivotovsky, Boris
    Zhong, Qing
    Zhou, Cong-Zhao
    Zhu, Changlian
    Zhu, Wei-Guo
    Zhu, Xiao-Feng
    Zhu, Xiongwei
    Zhu, Yuangang
    Zoladek, Teresa
    Zong, Wei-Xing
    Zorzano, Antonio
    Zschocke, Jürgen
    Zuckerbraun, Brian
    Guidelines for the use and interpretation of assays for monitoring autophagy2012Inngår i: Autophagy, ISSN 1554-8627, Vol. 8, nr 4, s. 445-544Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

  • 47.
    Koch, Andrea
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US.
    Gustafsson, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sörenson, Sverre
    Linköpings universitet, Institutionen för medicin och hälsa, Lungmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US.
    Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry2011Inngår i: Diagnostic Cytopathology, ISSN 8755-1039, E-ISSN 1097-0339, Vol. 39, nr 3, s. 188-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) expression may be a prognostic factor in lung cancer. In previous studies, COX-2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX-2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX-2-stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1-10% in 7 patients, 11-50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX-2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX-2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX-2-positive cells among patients and in the intensity of staining among individual cells in many single cases. Diagn. Cytopathol.2011;39:188-193. © 2010 Wiley-Liss, Inc.

  • 48.
    Kurz, Tino
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Brunk, Ulf
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Cell sensitivity to oxidative stress is influenced by ferritin autophagy2011Inngår i: FREE RADICAL BIOLOGY AND MEDICINE, ISSN 0891-5849, Vol. 50, nr 11, s. 1647-1658Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To test the consequences of lysosomal degradation of differently iron-loaded ferritin molecules and to mimic ferritin autophagy under iron-overload and normal conditions, J774 cells were allowed to endocytose heavily iron loaded ferritin, probably with some adventitious iron (Fe-Ft), or iron-free apo-ferritin (apo-Ft). When cells subsequently were exposed to a bolus dose of hydrogen peroxide, apo-Ft prevented lysosomal membrane permeabilization (LMP), whereas Fe-Ft enhanced LMP. A 4-h pulse of Fe-Ft initially increased oxidative stress-mediated LMP that was reversed after another 3 h under standard culture conditions, suggesting that lysosomal iron is rapidly exported from lysosomes, with resulting upregulation of apo-ferritin that supposedly is autophagocytosed, thereby preventing LMP by binding intralysosomal redox-active iron. The obtained data suggest that upregulation of the stress protein ferritin is a rapid adaptive mechanism that counteracts LMP and ensuing apoptosis during oxidative stress. In addition, prolonged iron starvation was found to induce apoptotic cell death that, interestingly, was preceded by LMP, suggesting that LMP is a more general phenomenon in apoptosis than so far recognized. The findings provide new insights into aging and neurodegenerative diseases that are associated with enhanced amounts of cellular iron and show that lysosomal iron loading sensitizes to oxidative stress.

  • 49.
    Kågedal, Katarina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Uno
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Heimlich, Gerd
    Institute for Medical Microbiology, Immunology and Hygiene, University of Köln, Köln, Germany.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
    Wang, Nancy S.
    Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
    Jürgensmeier, Juliane M.
    Institute for Medical Microbiology, Immunology and Hygiene, University of Köln, Köln, Germany.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomal membrane permeabilization during apoptosis: Involvement of Bax?2005Inngår i: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 86, nr 5, s. 309-321Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bcl-2 family members have long been known to control permeabilization of the mitochondrial membrane during apoptosis, but involvement of these proteins in lysosomal membrane permeabilization (LMP) was not considered until recently. The aim of this study was to investigate the mechanism underlying the release of lysosomal proteases to the cytosol seen during apoptosis, with special emphasis on the role of Bax. In human fibroblasts, exposed to the apoptosis-inducing drug staurosporine (STS), the release of the lysosomal protease cathepsin D to the cytosol was observed by immunocytochemistry. In response to STS treatment, there was a shift in Bax immunostaining from a diffuse to a punctate pattern. Confocal microscopy showed co-localization of Bax with both lysosomes and mitochondria in dying cells. Presence of Bax at the lysosomal membrane was confirmed by immuno-electron microscopy. Furthermore, when recombinant Bax was incubated with pure lysosomal fractions, Bax inserted into the lysosomal membrane and induced the release of lysosomal enzymes. Thus, we suggest that Bax is a mediator of LMP, possibly promoting the release of lysosomal enzymes to the cytosol during apoptosis.

  • 50.
    Kågedal, Katarina
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Scott Kim, Woojin
    Prince of Wales Medical Research Institute.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Chan, Sharon
    Prince of Wales Medical Research Institute.
    Cheng, Danni
    Prince of Wales Medical Research Institute.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Geriatriska enheten.
    Barnham, Kevin
    University of Melbourne.
    McCann, Heather
    Prince of Wales Medical Research Institute.
    Halliday, Glenda
    Prince of Wales Medical Research Institute.
    Garner, Brett
    Prince of Wales Medical Research Institute.
    Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimers disease2010Inngår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1801, nr 8, s. 831-838Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Niemann-Pick type Cl (NPC1) protein mediates the trafficking of cholesterol from lysosomes to other organelles. Mutations in the NPC1 gene lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC disease. Several parallels exist between NPC disease and Alzheimers disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles, and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not been investigated so far. In the present study, we measured NPC1 mRNA and protein expression in three distinct regions of the human brain, and we revealed that NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippocampus of 12-month-old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 12-month-old wild type mice, whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippocampus indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP or by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippocampus from AD patients compared to control individuals, and it is therefore possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.

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